Huntington's disease is the third most common degenerative brain disease after Alzheimer's disease and Parkinson's disease. It is a rare intractable inherited disease characterized by disorder in motion and cognition due to the degeneration of brain cells. The cause of Huntington's disease is the mutation of the Huntingtin gene located on chromosome 4 due to abnormally increased CAG repeat sequences. It is known that this mutation causes Huntington's disease by resulting in death of nerve cells [Di Prospero and Fischbeck; Nature Reviews Genetics (2005) 6:756-765].
Normal people have 35 or less CAG repeats. If the number of the CAG repeats is 36 or larger, there is a risk of Huntington's disease. And, if it is 40 or larger, there is a high risk of Huntington's disease. It is known that the disease occurs at younger ages as the number of the CAG repeats is larger. 60 or more CAG repeats were found in patients who were diagnosed with Huntington's disease in adolescence.
Xenazine (tetrabenazine) is the representative drug used for patients with Huntington's disease. However, Xenazine merely reduces movement disorder by decreasing the level of dopamine in the body and cannot fundamentally treat the chromosome anomaly which is the cause of Huntington's disease. It was reported that increased trimethylation at histone H3 lysine 9 (H3K9) was observed in the brain tissue of a patient who died of Huntington's disease and that ESET (a.k.a. SETDB1) is the important enzyme that trimethylates H3K9. ESET stands for ERG-associated protein with SET domain, where ERG means erythroblast transformation specific-related gene (ETS-related gene), and SETDB1 stands for SET domain bifurcated 1 (hereinafter, referred to as ‘ESET/SETDB1’). ESET/SETDB1 was reported as a molecular target for treatment of Huntington's disease because increased R6 mouse survival time was found in the R6 model which is an animal model of Huntington's disease when the expression of ESET/SETDB1 was inhibited (PNAS, 2006, 103, 19176-19181). At present, no compound is known as an ESET/SETDB1 inhibitor and there is a need for development of an ESET/SETDB1 inhibitor for treatment of Huntington's disease.